COSA:NETs guidelines/Cytotoxic chemotherapy and other systemic treatments
|Information on authorship and revision|
|Last reviewed:||November 2010|
|Author(s):||Dragan Damianovich (Chair), Tim Price, Michael Michael,
Winston Liauw, Yu Jo Chua, David Goldstein,
Cytotoxic chemotherapy and other systemic treatments
Chemotherapy traditionally has had a limited role in the treatment of neuroendocrine tumours (NETs). However, some newer, targeted agents in particular, have shown a significant activity, which has broadened systemic therapeutic options for this disease.
Chemotherapy is mainly used in patients with progressive and metastatic pancreatic NETs after failure of other treatment modalities such as somatostatin analogues (SSAs) e.g. octreotide LAR. To date there is no evidence to support its use in adjuvant settings (after complete resection of the disease).
Tumour grade (determined by histological appearance, Ki-67 and mitotic index) may be useful for selecting systemic treatments. For example, chemotherapy may be more beneficial in high grade or poorly differentiated tumours whereas SSAs or targeted therapies may be preferable as early treatment for well differentiated disease.
Patients progressive on standard treatment should be offered participation in clinical trials.
High grade tumours
High grade tumours are poorly differentiated with high proliferative/mitotic indices [>20 mitoses/10 HPF; Ki-67 index >20%]. They are usually metastatic at presentation and chemotherapy may be the only treatment option. High grade tumours are often managed similarly to small cell lung cancer.
In spite of lack of evidence, patients with resected high grade tumours and without evidence of residual disease are often offered ‘adjuvant’ chemotherapy. Consideration should also be given to radiotherapy in close or positive surgical margins. Extrapolating the data from the treatment of limited stage small cell lung carcinoma concurrent chemo and radiotherapy may be considered.
Low grade tumours
Heterogeneity of tumours of so called low grade potential is widely recognised. In spite of their well differentiated appearance on histology they can sometimes have an aggressive clinical course. Their behaviour may not only be variable between patients but also in an individual patient during the course of the disease. The decision to initiate systemic treatment should depend on factors such as the rate of disease progression and burden of disease related symptoms, whereas factors such as site of origin (pancreatic versus non-pancreatic), appearance on functional imaging, treatment history and treatment availability should be considered when choosing between treatments.
Metastatic tumors with low mitotic/proliferative indices [<2 mitoses/10 HPF; Ki-67 index <3%] can be slow growing and asymptomatic, and may not require systemic treatment for some time. Moderately differentiated (low grade malignant) tumors with intermediate mitotic/proliferative indices [2–20 mitoses/10 HPF; Ki-67 index 3–20%] have more uncertain behaviour requiring closer observation and sometimes earlier start of systemic treatment. Functional imaging (octreoscan and/or FDG PET) may help in choosing the type of systemic treatment. Intermediate grade NETs with octreotide non-avid but FDG PET positive lesions may require more aggressive chemotherapy regimens traditionally used in high grade NETs.
Somatostatin analogues may be considered as earlier-line systemic therapy in metastatic octreotide-avid with existing data suggesting anti-proliferative action in both midgut and pancreatic NETs of lower proliferative index (Ki67<10%).
Efficacy of targeted agents such as sunitinib (reimbursed by the Australian Pharmaceutical Benefits Scheme, but not by Pharmac in New Zealand) and everolimus have also been shown in randomised trials in pancreatic NETs, and in these tumours may be considered prior to chemotherapy. Although data on optimal sequencing is not yet available the results from the aforementioned randomised trials appears more compelling than those of earlier studies of cytotoxic regimens, and some targeted agents may be better tolerated than some cytotoxic regimens.
Cytotoxic chemotherapy should still be considered after failure of these newer agents, or when they are not available. NETs of pancreatic origin are often more responsive to chemotherapy than non-pancreatic NETs. Streptozocin based regimens have been traditionally used in the majority of patients with pancreatic NETs. A randomised phase III study by Moertel et al in 1992 showed advantage for streptozocin and doxorubicin over streptozocin and 5-FU doublet with impressive response rate (69% vs 45%), response duration (20 vs 6.9 months) and median survival (26 vs 18 months). Although further studies did not confirm the initial results (response rates 36-55%), streptozocin in combination with 5-FU and/or doxorubicin has been the standard of care for years. Similar chemotherapy regimens in non-pancreatic NETs have shown less impressive results.
More recently several newer chemotherapy regimens (dacarbazine, temozolomide and thalidomide or capecitabine) have shown promising activity. Similar to streptozocin based regimens they seem more effective in pancreatic than non-pancreatic NETs (dacarbazine 33% and 16%, temozolomide alone 14% and temozolomide with thalidomide 45% and 25%, respectively). Similar to the treatment of glioblastomas, temozolomide is much more active in tumours lacking DNA repair enzyme MGMT with 51% response rates in pancreatic NETs. The addition of capecitabine (an oral 5-FU prodrug) to temozolomide has shown promising activity in previously untreated pancreatic NETs in retrospective analyses and deserves prospective validation.
Due to its significant potential for side effects (myelosuppression, fatigue, depression, thyroid dysfunction, autoimmune syndromes) interferon alpha is rarely used as a front line treatment for NETs. When used as a single agent it achieves modest response rates (<10% RR, <25% SD) and it is inferior to SSAs in controlling tumour-related symptoms. However, in its usual dose (3-9 mega units / 3-5 times per week) it may have a role in control of hypersecretion symptoms in combination with SSAs when they are not sufficiently controlled with SSAs.
Monitoring of treatment response
Urine 5-HIAA is most useful for monitoring serotonin secreting tumours (midgut NETs). It is elevated in >70% of patients. Higher levels can be expected in functioning and more advanced tumours. Malabsorption syndromes and tryptophan reach food can affect its level in urine.
Serum Chromogranin A
Serum Chromogranin A (CgA) is a more sensitive marker than 5-HIAA in detection and monitoring of both functioning and non-functioning NETs (87% vs 73%). Again the levels are higher with more advanced tumours. Proton pump inhibitors can elevate serum CgA and should be withheld before the test.
CT and Octreoscan have been traditionally used for staging and monitoring of treatment effects in NETs. Wherever possible triphasic CT should be used since it is more accurate in defining liver lesions. It is less clear when Octreoscan should be used. If it is available it should be used at diagnosis and when PRRT treatment is considered. FDG PET avidity is more likely in high grade tumours and may predict responsiveness to platinum/etoposide chemotherapy. Emerging evidence suggests that galium PET/CT may become the imaging method of choice in the future.
NETs are highly vascular and are known to express vascular endothelial growth factor (VEGF) and its receptor (VEGFR). Agents targeting the VEGF axis (e.g. sunitinib) and its downstream serine/threonine kinase mammalian target of rapamycin (mTOR) (e.g. everolimus) have shown a significant activity in recently published reports of randomised studies.
VEGF / VEGFR inhibitors
Several VEGF and VEGFR tyrosine kinase inhibitors have been been studied mostly in pancreatic NETs. Significant reduction of tumour blood flow and improvement of PFS at week 18 (95% vs 68%; p=0.02) was noted with bevacizumab (monoclonal anti-VEGF Ab) when compared to pegylated interferon alpha. When combined with temozolomide, bevacizumab showed impressive disease control rate (PR+SD) in both pancreatic and non-pancreatic NETs (94% and 92%, respectively). As expected there were more partial responses observed in pancreatic NETs (24% vs 0). An impressive, although unconfirmed, PR rate (60%) was reported in a small number of patients with progressive NETs with combination of bevacizumab and FOLFOX. However, the patients with high grade tumours were also included in analysis.
Sunitinib, a multikinase inhibitor (VEGFR, PDGFR, RET, c-Kit), achieved overall objective response rate of 16.7% in pancreatic and 2.4% in non-pancreatic NETs in an early study. In that study, median time to progression however, was longer in non-pancreatic then pancreatic NETs (10.2 and 7.7 months respectively), although one year survival rates were similar for both cohorts. A recently published report of randomised trial of sunitinib versus placebo which enrolled patients with progressing advanced pancreatic neuroendocrine tumours has shown a significant improvement in progression free (11.4 vs 5.5 months, hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; p<0.001). With longer term follow up, the overall survival improvement which was initially observed is no longer statistically significant, although a trend towards survival benefit is still suggested.
Sunitinib is funded in Australia (but not in New Zealand) for the treatment of metastatic or unresectable well-differentiated malignant pancreatic neuroendocrine tumours in patients who are symptomatic despite SSA therapy or have documented disease progression.
Evidence of mTOR involvement in pathogenesis of NETs is suggested by association of germline mutations in the mTOR pathway with NETs. Both of the currently available mTOR inhibitors, temserolimus and everolimus (RAD001) have been studied in patients with NETs.
Temserolimus has shown a modest objective response rate of 5.6% in a phase II study but higher baseline levels of phosphorylated mTOR (p=0.01) predicted for a better response. An increase in pAKT and decrease in phosphorylated mTOR after the treatment correlated well with increased time to progression.
Everolimus showed a promising ORR (20%) and median PFS (60 weeks) in initial phase II study.  In a follow-on international phase II study (RADIANT-1) patients with advanced pancreatic NETs progressing after chemotherapy, were divided into two strata, everolimus alone (n=115) or everolimus plus octreotide (n=45) on the basis of whether the patients were receiving octreotide at study entry. The median PFS for patients receiving everolimus or everolimus and octreotide were 9.7 and 16.7 months, respectively. An early biomarker response (30% decrease or normalisation of CgA or NSE at week 4) correlated with superior PFS. Everolimus (RAD001) has been shown to significantly improve progression free survival in metastatic pancreatic neuroendocrine tumours in a randomised phase III trial (RADIANT-3) compared to placebo (11 versus 4.6 months, hazard ratio for disease progression and death, 0.35; 95% CI 0.27 to 0.45; p<0.001), although no overall survival improvement was observed. Crossover to everolimus in the placebo arm was allowed in the study, which does make overall survival difficult to interpret. Benefit is also suggested in a similar randomized study in patients with non-pancreatic neuroendocrine tumours and a history of the carcinoid syndrome, in which patients were treated with Sandostatin LAR with or without everolimus. Although this study did not meet its primary end point of an improvement in central review evaluated progression-free survival (hazard ratio 0.77, but p=0.026, above pre-set cut off of 0.0246), there was still a clinically meaningful 5.1 month progression-free survival difference between arms, and progression free-survival by investigator review was significantly improved; interpretation of the overall survival results are also complicated by crossover.”
In metastatic well and intermediate differentiation pancreatic neuroendocrine tumours, the clear improvement in outcomes observed with the use of agents such as sunitinib and everolimus may make these agents preferable to chemotherapy earlier in the course of managing these patients.
Sunitinib and everolimus are not currently funded in New Zealand for the treatment of NETs and therefore are not available to the patients in the public system.
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